Fragile X Syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of function of the Fragile X Mental Retardation Protein (FMRP). Studies of FXS patients and mouse models of FXS suggest that FMRP is critical for proper synaptic function and plasticity. I propose to investigate the role of FMRP in synaptic function through three major aims: 1) Electrophysiological measurements of synaptic function following transient alteration of FMRP expression levels in organotypic hippocampal slice cultures (OHSCs) and through the use of FMRP mutants; 2) Electrophysiological analysis of synaptic plasticity in FMRP-overexpressing mice and in OHSCs following transient overexpression of FMRP and FMRP mutants; and 3) Biochemical analysis of glutamate receptor expression and trafficking in FMRP-overexpressing and FMRP-knockout mice and in OHSCs following transient alterations in FMRP expression. This research should give substantial insight into the role of FMRP at the synapse and may provide impetus for the generation of a treatment for FXS. [unreadable] [unreadable]